Although the symptoms and effects of EPM have been recognized since the 1970's, it was not until 1991 that the protozoan parasite that causes EPM was cultured from a horse and given the name Sarcocystis neurona. The horse is an aberrant, dead-end host, as infectious forms of the parasite are not passed from horse to horse or from infected horse to a definitive or true intermediate host. Recent investigations indicate that the feces of the opossum (the definitive host) are the source of the infection for horses.
EPM occurs in much of North America. Serologic surveys conducted in central Kentucky, one county in Pennsylvania, and the entire states of Ohio and Oregon, have revealed that approximately fifty percent (50%) of the horses in the surveyed areas have been exposed to the above-noted protozoan parasite. A positive serum test indicates exposure to the parasite, not necessarily the presence of an active form of the disease. The incidence of the active disease is much lower.
In studies that looked at the distribution of seropositive cases geographically, it was found that climatic factors may affect exposure rates; i.e., an increase of freezing days or a very hot environment was associated with a decrease in the numbers of horses exposed to the parasite. EPM appears to have a sporadic distribution, although outbreaks have occurred on farms in Kentucky, Ohio, Indiana, Michigan and Florida.
A horse of any age, breed, or sex may be affected by EPM. The disease has occurred in a horse of two months of age, as well as one in its thirties. In fact, any horse demonstrating neurologic abnormalities should be considered a candidate for EPM affliction.
Clinical signs of the condition depend on the location of the organism within the central nervous system. These signs include weakness, malposition of a limb, muscle atrophy, spinal ataxia, or "wobbling" and/or head tilt with asymmetry of the face (e.g., eyelid, ear, or lip). A severely EPM-affected horse may become recumbent and unable to rise. Lameness not traceable to orthopedic disease or any combination of the above signs may occur with EPM. Other unusual signs may also occur.
In most cases, an affected horse is bright and alert with a normal appetite, although it may be dysphagic (i.e., unable to eat) and may act as if it is choked with feed material coming from its nose. Hematological and biochemical blood values are usually in the normal range.
Diagnosis of EPM is based on clinical signs and on testing of the horse's cerebrospinal fluid (CSF). Originally, the diagnosis was based on the presence of antibodies to Sarcocystis neurona in serum, though it is now known that a positive serum test cannot be used to make a diagnosis; such positive serum test simply indicates exposure to the parasite, not necessarily presence of the disease. Cerebrospinal fluid testing is now believed to be the most useful test to assist in the diagnosis of this disease in a live horse.
Currently available treatment of horses with EPM is expensive and typically requires a duration of at least ninety (90) days. In some cases, treatment lasts indefinitely. This current treatment involves the adaptation of tablets intended for human use. Thus, pyrimethamine tablets are administered along with tablets containing a trimethoprim-sulfonamide combination. Typically, the two types of tablets are crushed and placed in suspension for oral administration. These medications should be administered one hour prior to feeding hay and are accompanied with frequent, periodic, veterinary, neurologic examinations during the treatment period.
Discontinuation of therapy is usually based on the administration of medication thirty days beyond the plateau of clinical improvement or disappearance of antibody to the protozoa from the CSF. Suboptimal dosing or intermittent therapy has no proven efficacy.
Adverse effects of therapy may include anemia, abortion, diarrhea and low white blood cell counts. Both medications for treatment of EPM inhibit folic acid metabolism. Unlike horses, however, the protozoan is unable to utilize pre-formed folic acid. Supplementation with folic acid or folinic acid (40 mg orally, once a day) and/or brewer's yeast may help prevent adverse side effects. It is suggested, however, that folic acid not be administered at the same time as the pyrimethamine because of competitive inhibition and absorption.
The gametocytocidal and sporontocidal effects of 2 g sulfadiazine with 50 mg pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum is disclosed in Chemical Abstracts, Volume 69: 50900p (1968). Primaquine diphosphate, pyrimethamine and sulfadiazine were said to show causal prophylactic activity against rodent malaria, Plasmodium berghei yoelii, as disclosed in Chemical Abstracts, Volume 77: 109339h (1972). A three component composition of pyrimethamine, sulfadiazine and cycloguanil-HCl for treating rodent malaria is disclosed in Chemical Abstracts, Volume 96: 40845t (1982). Similarly, sulfadiazine sodium has been used to enhance the activities of certain antiinfective drugs against infections caused by pyrimethamine-susceptible or pyrimethamine-resistant strains of P. falciparum and P. vivax in owl monkeys. See, Chemical Abstracts, Volume 92: 15581p (1980).
There are a number of articles describing the treatment of Toxoplasma gondii with pyrimethamine and sulfadiazine, but at a ratio that uses a very large amount of sulfadiazine relative to pyrimethamine. See, e.g., Chemical Abstracts, Volume 78: 52708s (1973) (1 mg/kg pyrimethamine and 100 mg/kg sulfadiazine for mice); Chemical Abstracts, Volume 85: 72303d (1976)(2 mg/kg pyrimethamine and 100 mg/kg sulfadiazine for cats); Chemical Abstracts, Volume 99: 133330y (1983); Chemical Abstracts, Volume 101: 87339t (1984); Chemical Abstracts, Volume 122: 45806w (1995) (1 mg/kg pyrimethamine and 50 mg/kg sulfadiazine for monkeys); Chemical Abstracts, Volume 122: 253089n (1995). Chemical Abstracts, Volume 123: 102131u (1995) describes the daily administration of 25 mg pyrimethamine and a total of 2 g sulfadiazine to prevent toxoplasmic encephalitis relapse in AIDS patients.
The patent literature includes many descriptions of methods for treating protozoan-mediated diseases. McHardy, in U.S. Pat. No. 5,273,970, states that a protozoal disease, toxoplasmosis, may be controlled to a certain extent using pyrimethamine together with a sulfonamide. This patent asserts that baquiloprim can be used for the treatment and/or prophylaxis of protozoal infections in animals, including humans. Although the baquiloprim can be used as the sole active ingredient, it can be co-administered with a sulfonamide. A long list of suitable sulfonamides is provided, most preferably sulfadiazine, sulfamethoxazole, sulfadimethoxine, sulfadoxine, sulfamoxole, or sulfadimidine.
In U.S. Pat. No. 4,599,416, granted to Kompis, a process for the preparation of aqueous compositions of sulfonamides and sulfonamide potentiators for the treatment of bacterial infections in humans and animals is described. A long list of potential sulfonamides is provided. The "potentiators" are described as denoting compounds that increase the antibacterial activity of sulfonamides more than additively. An equally long "laundry" list of such potentiators is provided, which includes trimethoprim and pyrimethamine. Other patents dealing with protozoan parasites include: U.S. Pat. No. 4,293,547, granted to Lewis et al. for the treatment of malaria; U.S. Pat. No. 4,340,609, granted to Chou (various protozoal infestations); U.S. Pat. No. 4,368,193, granted to Argoudelis et al. (malaria); U.S. Pat. No. 4,728,641, granted to Tubaro et al. (protozoal infections generally); U.S. Pat. No. 4,992,444, granted to Stevens et al. (trypanosomes and malaria); and U.S. Pat. No. 5,486,535, granted to Marr et al. (Toxoplasma gondii).
Beech, in Veterinary Medicine/Small Animal Clinician, pp. 1562-1566 (December 1974) described a condition in eight (8) horses with signs of neurological disorder. On the assumption that toxoplasmosis was involved, the author suggested that pyrimethamine and sulfadiazine, used successfully against toxoplasma in man, might be useful in horses.
Welsch, B. B. recommended the use of pyrimethamine (0.5 mg/kg), combined with a 20 mg/kg two-part mixture of sulfadiazine (16.7 mg/kg) and trimethoprim (3.3 mg/kg), to treat horses suffering from EPM. See, Welsch, B. B., in The Compendium North American Edition, Equine, Morris, D. D. (Ed.) (1991) pp. 1599-1602.
Two articles by Clark et al., which appeared in American Journal of Veterinary Research, Volume 53, Number 12, pages 2292-2295 and 2296-2299 (December 1992), discuss the pharmacokinetics of intravenously and orally administered pyrimethamine in horses. The first article, at page 2292, states that clinical reports indicate the possible value of treatment of horses with protozoal encephalomyelitis with pyrimethamine in combination with trimethoprim and sulfonamides. On the other hand, the second article, at page 2299, concludes that the oral administration of 1 mg pyrimethamine/kg once a day for 10 days apparently does not present a serious toxicological problem to horses.
Hence, despite a great deal of past and on-going effort, there remains an unfulfilled need for a treatment for EPM-afflicted equines, particularly horses, which is not only effective but is also convenient to administer to maximize compliance and reduce the emergence of resistant strains. In particular, prior compositions for the treatment of EPM involve three-component mixtures, including pyrimethamine, sulfadiazine and trimethoprim. Moreover, where prior compositions contained pyrimethamine and sulfadiazine as the active ingredients, such compositions used very small ratios of pyrimethamine to sulfadiazine limiting their effectiveness to treating malaria only and hampering their usefulness in other pathological conditions, like protozoan-mediated diseases, especially EPM. The fact is that there is currently no approved drug or drug combination for the treatment of EPM.